february 16, 2005 - princeton university
TRANSCRIPT
1
B-Alkyl Suzuki Couplings
MacMillan Group MeetingNicole Goodwin
February 16, 2005
B-Alkyl Suzuki CouplingsOutline
! Mechanism of the general Suzuki Coupling with Pd(0)
! Introduction
Relevant and Comprehensive Reviews:
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. "The B-alkyl Suzuki-Miyaura cross-coupling reaction: a versatile C–C bond-forming tool." Angew. Chem. Int. Ed. 2001, 40, 4544-4568.
Miyaura, N. "Metal-Catalyzed Cross-Coupling Reactions of Organoboron Compounds with Organic Halides." Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley-VCH, Weinheim, 1998, Ch. 2.
Miyaura, N; Suzuki, A. "Transition-Metal Systems Bearing a Nucleophilic Carbene Ancillary Ligand: fromThermochemistry to Catalysis." Chem. Rev. 1995, 95, 2457-2483.
! Reaction Scope with B-alkyl substrates
! oxidative addition
! transmetalation - emphasis on B-alkyl systems
! phosphine ligand effects
! reductive elimination
! nickel
! Synthesis of alkyl boranes and borates - hydroboration
! Aryl and Vinyl Halides and Triflates
! Potassium alkyltrifluoroborates
! Aryl chlorides
! Alkyl halides and triflates
! Macrocyclization
! Asymmetric system
Echavarren, A.M.; Cardenas, D. J. "Mechanistic Aspects of Metal-Catalyzed C,C- and C,X-Bond-Forming Reactions." Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley-VCH, Weinheim, 1998, Ch. 1.
! B-alkyl Suzuki couplings in natural products
2
B-Alkyl Suzuki CouplingsAbbreviations
9-BBN-H9-borabicyclo[3.3.1]nonane
B
OBBD9-oxa-10-borabicyclo[3.3.2]decane
B
O
BpinB-pinacol
B
O
O
BcatB-catechol
B
O
O
FePPh2
PPh2 PPh2 PPh2
Ph2P PPh2
dppfbis(diphenylphosphanyl)ferrocene
dpppbis(diphenylphosphanyl)propane
dppebis(diphenylphosphanyl)ethane
Ph
O
Ph
dbadibenzylideneacetone
codcyclooctadiene
acacacetylacetonate
Me
O
Me
O
Me
O
Me
OM
! Some ligands
! Boron substituents
3
Why Boron?
! The appeal of the Suzuki coupling can be attributed to
! mild and versatile methods for synthesizing boranes
! commercial availability of boronates and boronic acids
Aldrich and Frontier Scientific sell over 100 boronic acids each
! air-stable
! water tolerant
! non-toxic nature of starting materials and borate by-products
! Drawbacks to the B-alkyl Suzuki couplings
! not air-stable
! trialkylboranes must be synthesized in situ without isolation
! not commercially available
10 alkyl boronic acids/esters available, only 1 alkyl BBN available
! tolerance of a broad range of function groups
! easy incorporation of non-transferable boron ligands
B
The Catalytic Cycle
! The catalytic cycle of the Suzuki-Miyaura alkyl coupling is similar to other metal-catalyzed couplings
Pd(0)
R1 Pd(II) X
R1 X
R1 Pd(II)
B(OH)2 + baseB(OH)3
R1 R2
oxidative addition
transmetallation
reductive elimination
R2
R2R2 !-H elimination
H
Pd R2
R1
Ln
! The B-alkyl Suzuki coupling is effected by all reaction partners
! type of organoborane
! type of aryl/alkenyl/alkyl halide
! metal catalyst! base
! solvent
4
The Catalytic Cycle
! Competition experiments determined the order of reactivity for oxidative addition
I >> Br > OTf >> Cl
Oxidative Addition
! Bidentate ligands keep a cis complex (also a huge factor in facilitating reductive elimination and thus preventing of !-H elimination of alkyl–M complexes)
L Pd X
R1
L
R1 Pd X
L
LPd(0)LnR1 X
L Pd X
R1
L
R1 Pd X
L
LPd(0)LnR1 X
L
L
LUMOHOMO
Cl Br I
M
! Qualitative FMO picture
5
What About Nickel?
! 2 mechanisms for rate-determining oxidative addition
Ni
X
L
L
! charged intermediate as seen for Pd(0), explains behavior of Hammett studies
! 1 electron oxidation of a Ni(II) to a Ni(III) was shown to occur at Pt electrodes
LnNi(0) ArXe–
[LnNi+][ArX–] LnNi(I)X Ar ......
LnNi(I)X ArX LnNi(III)ArX2
(III)Ni
X
X
(II)Ni
Ar
X L
LnNi(III)ArX2 LnNi(II)ArX LnNi(II)X2 LnNi(III)Ar2X
(III)Ni
X
X
(II)Ni
Ar
X LL
LnNi(III)Ar2X LnNi(I)XAr–Ar
Radical Pathway Studies: Kochi, J. K. Pure Appl. Chem. 1980, 52, 571.
initiation
! inhibition occurs in the process upon the addition of one-electron acceptors that form stable radicals (quinones, nitroaromatics)
6
Oxidative AdditionThe Role of Electron-Rich, Bulky Phosphines
! Electron-rich phosphines can stabilize the oxidative addition intermediate through agosticand C! interactions with the C–H bond and a palladium d orbital
P
Pd H
Br
t-Bu
t-Bu
2.27Å
P
Pd H
Br
t-Bu
t-Bu
2.33ÅMe
Me
Me
Me
! facilitate transmetalation and reductive elimination processes
PCy2Pd
O
Ph
Ph2.323 Å
! Pd/P(t-Bu)3-based catalyst system has an unprecedented selectivity for aryl chlorides
TfO Cl
Me
(HO)2B
1.5% Pd2(dba)33% P(t-Bu)3
3 equiv. KFTHF, RT
Me
TfO 95%
changing the ligand to PCy3 results in exclusive oxidative addition on the C–OTf bond
Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
! C! interactions betweenortho-aryl groups and palladium is also noted in a seemingly bidentate system by Kocovsky, et al. (J. Am. Chem. Soc. 1999, 121, 7714.)
NMe2
PPh2
NMe2
PPh2
NMe2
Ph2P
PdCl2 PdCl2PdCl2
10% 85% 5%
observations made by31P NMR and X-ray
crystallography
Oxidative Addition of Alkyl Halides
! !-H elimination strikes again
Pd(0)
Pd(II) X
X
oxidative addition
R
R
Pd(II) XR
H
H
R
slow
! Oxidative addition intermediate is unstable electron-rich ligands help stabilize
Ph Br
L Pd L
L Pd L
Br
Ph
Et2O
0 °CL = P(t -Bu)2Me
! With electron-rich phosphines, Fu is able to effect oxidative addition under mild conditionsand obtain an x-ray crystal of the intermediate
L Pd L
Br
Ph
50 °CPh
Fu, G. C. et al. J. Am. Chem. Soc. 2002, 124, 13662.
7
Oxidative Addition of Alkyl Halides
! Oxidative addition of C(sp3)–X to Pd(0) is usually via an associative bimolecular process (Sn2)
! Exact mechanism of oxidative addition is not known
CXPd(0)
C Pd(0) C Pd(II)
X
! radical and concerted nucleophilic addition mechanisms have been proposed
"The mechanism of the oxidative addition reaction to a coordinatively unsaturated species is controversial,and indeed different mechanisms may be operating depending on the alkyl group, the halogen, the phosphine
ligands, and the metal."
- J. Stille, "Mechanisms of Oxidative Addition of Organic Halides to Group 8 Transition Metal Complexes". Acct. Chem. Res. 1977, 10, 439.
! Allylic electrophiles are a whole different scenario
! convoluted by competing Sn2' pathways
! usually goes with inversion in polar, coordinating solvents
! stereochemistry tends to be retained in non-coordinating solvents (benzene, CH2Cl2)
CO2Me CO2Me CO2Me
PhCl Ph
Pd(0)
M–Ph
benzene
MeCN
96
0
4
100
The Catalytic Cycle
! Soderquist and Woerpel independently show transmetallation goes with retention of stereochemistry.
Stereochemistry of Transmetallation
! Alkyl boranes will not couple without added base - what is really happening in the transmetallation step?
D
D9-BBN-D;
CD3CO2D60% yield
9-BBN-H Hb DBR2
DHa
Ja,b (1H NMR) = 4.8 Hz
Pd(PPh3)4
NaOH, PhBr85%
92%
Hb DPh
DHa
Ja,b = 4.8 Hz
D
Hb9-BBN-H;
CD3CO2D60% yield
9-BBN-D Hb DBR2
HaD
Ja,b = 12.3 Hz
Pd(PPh3)4
NaOH, PhBr89%
92%
Hb DPh
HaD
Ja,b = 12.3 Hz
Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458. Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
8
The Catalytic Cycle
! Effects of base on the alkyl borane substituent
Mechanism of Transmetallation
! Soderquist proposes a µ2-hydroxo-bridged transition state to account for stereochemistry retention
Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
O
Pd C
B
H
R'L
L
O B
R
H
Pd
R'L
L
B
RPd
R'L
LO
H
BC6H13
B
C6H13
HOOH
!(11B) = 87.7 !(11B) = 3.3
BC6H13
BC6H13
OH
!(11B) = 54.1 not observed
O O
What is the role of the base in the Suzuki-Miyaura coupling??
the base makes the alkylborane coupling distinct from boronic acids and esters
Which pathway is it to the intermediate?
Ph-Br hexyl-BBNPd(PPh3)4
NaOH, THFPh-hexyl+ 1 equiv. NaOH (75%)
2 equiv. NaOH (100%)
John Soderquist
The Catalytic Cycle
! Effects of base are not as pronounced with 9-OBBD systen
Mechanism of Transmetallation
! Effects of base on palladium catalyst
Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
BC6H13
O
PdL4 PdL3 PdL2 L2PdPh
BrL2Pd
Ph
OH
– L
L = PPh3
– L PhBr OH
!(31P) = 18 ! = 26.1 ! = 23.6
27 °C
33% - 2h, 27 °C90% - 2h, 65 °C
Ph-Br
Pd(PPh3)4
NaOH, THFPh-hexyl 1 equiv. NaOH (92%)
2 equiv. NaOH (100%)
! Base is consumed in the formation of the hydroxy "ate" complex
B
R
HOB
HOB
OH
HOL2PdPh
– PhR
OH
!(11B) = 56.3 !(11B) = 9.6
9
The Catalytic Cycle
! New catalytic cycles proposed, emphasizing the importance of the base in the reaction
Mechanism of Transmetallation
! Five possible roles for the base in the cross-coupling
1. formation of hydroxyborate complexes
2. hydrolysis of Pd(II)X to monomeric Pd(II)OH
3. complexation of BBN-OH byproducts
4. catalyst regeneration
5. accelerated coupling rates for OBBD reactions
B
RPd
R'L
LO
H
O B
R
H
Pd
R'
LL
BR
O
BR
B
R
HO
PdL2
L2PdBr
L2PdOH
R1Br
OH
L2PdR
R1
R1
B
OH
HO
OH
R–R1
R1
OH
L2PdR
R1
BR
O
OH
ratedeterminingstep
rate determining
step
The Catalytic CycleRates of Transmetalation
! Unhindered, electron-rich alkyl boranes react most efficiently
R–BX2
PdCl2(dppf)
50 °CPhI Ph–R+
Entry Organoborane Base (equiv.) Solvent Yield
octyl BBN NaOH (3) THF/H2O 99%1
2
3
4
5
6
octyl B
2
NaOH (3) THF/H2O 93%
B
3
KOH (3) THF/H2O 93%
octyl B
O
O
octyl B
O
O
octyl B(OH)2
KOH (3)TlOEt (3)
Tl2CO3 (1.5)TlOH (3)
THF/H2OTHF/H2O
THFbenzene
trace41%93%84%
TlOH (3)Tl2CO3 (1.5)
THF/H2OTHF
34%trace
TlOH (3) THF/H2O trace
1° > 2°
! No examples of 2° alkyl borane coupling in preparative synthesis
ThX
10
Effect of Bases
! Effects of bases (MB) can be roughly estimated by the basic strength and affinity of M+ for halideions (stability constant).
! Bases with alkyl boranes/borates are solvent dependent
stability constants for X– (log K at 25 °C)
K+ Cs+ Ba2+ Bu4N+ Tl+ Cu+ Ag+
Cl–
Br–
I–
-0.7
–
-0.19
-0.39
0.03
-0.03
-0.13
–
–
0.40
0.49
0.78
0.49
0.91
–
2.7
5.9
8.9
3.3
4.7
6.6
reactions can be fast for M+ with high
stability constant
L2PdX
L2PdOH
R1 R1MOH
– MX
! strong bases (NaOH, TlOH, NaOMe) perform well in THF/H2O
! weaker bases (K2CO3, K3PO4) perform well in DMF
! Kishi is the first to observe the thallium effect (J. Am. Chem. Soc. 1989, 111, 7525)
TBSO
OTBS
TBSO
B(OH)2
TBSO
O
AcO
AcO
OAc
I
AcO
OMe
TBSO
OTBS
TBSO
TBSO
O
AcO
AcO
OAc
AcO
OMe
Pd(PPh3)4
baseTHF/H2O
23 °C
palytoxine
base cat(mol%) min. yield
KOH
Ag2O
TlOH
25
25
3
120
5
30
86%
92%
94%
The Catalytic Cycle
! Reductive elimination is not typically the rate determining step in cross-coupling
Reductive Elimination
! one exception is allylic electrophiles
– needs p-benzoquinone or other electron-withdrawing olefins to promote reductive elimination
Pd
Ar
L
+ olefin Pd
Ar
olefin
+ LAr
– bisallyl coupling is theorized to prefer a non-productive elimination
Pd
PR2
PR2
Pd
PR2
PR2
3
3'
3'
3
Cardenas, D. J.; Echavarren, A. M. et al. Chem. Eur. J. 2002, 8, 3620.
! Bidentate ligands can facilitate reductive elimination by forcing substituents cis
R2P
Pd
X
Y
PR2
R2P
R2P
R2P
Pd
PR2
Y
X
X Yred
elim
11
Hydroboration Allows Easy Access to Alkyl Boranes
! Hydroboration is highly chemo-, regio-, and stereoselective
! electron-rich, unhindered olefins react most rapidly
Ot-BuTMS
Me
MeMe CN
MeMe
MeMe
Me MeMe Me Br
Me
MeMe
Me
1615 300 196 100 5.9
1.13 0.68 0.32 0.011 0.006
! regiochemistry can be reversed with catalyzed and uncatalyzed systems
R R MeRBR2
BR2
H-BR2 H-Bcat
RhCl(PPh3)3
- changing to pinacolborane will give anti-Markovnikov product with Rh-system
- different substituents on olefin will effect product distribution
- Sm-catalysis gives anti-Markovnikov
Review on Catalytic, Asymmetric Hydroboration: Crudden, C. M.; Edwards, D. Eur. J. Org. Chem. 2003, 4695.
Hydroboration Allows Easy Access to Alkyl Boranes
! Hydroboration is highly chemo-, regio-, and stereoselective
! diastereoselective hydroborations - sensitive to steric and electronic factors
n-Bu
OTBS
Me
n-Bu
OTBS
Me
n-Bu
OTBS
Me
BR2 BR2
9-BBN
HBcat/RhCl(PPh3)3
90 : 10
4 : 96
Burgess, K. et al. J. Am. Chem. Soc. 1991, 113, 6139.
CH2MeH
R
RO
HBL2
approach from the most electron-rich face
CH2MeH
RO
R
H[Rh]
most EWG anti - stabilizes M-!* interaction via "*
! Alkyl lithium additions are used left frequently
R It-BuLi;
9-BBN-OMeR B
OMe
R BBS
TIPS
R MgBr
Marshall, J. A. et al. J. Org. Chem. 1998, 63, 7885. Soderquist, J. A. et al. Tet. Lett. 2000, 41, 3537.
12
RO
R
H
H
Hydroboration Allows Easy Access to Alkyl Boranes
! Hydroboration is highly chemo-, regio-, and stereoselective
! diastereoselective hydroborations - sensitive to steric and electronic factors
CH2MeH
R
RO
HBL2
approach from the most electron-rich face
! Quick comment on stereoselective hydroboration with substrate chirality
! electronic influence is shown by Houk to prefer approach of the borane from the most electron-rich
face (after A1,3 and A1,2 strain minimization)
MeH
R
OR
R
R
BLL
H
MeR
R
BLL
! without ether or hydroxyl substituents ! to the olefin, steric influence goes as expected with minimization
of A1,3 strain and approach from less-hindered face
H
MeH
RL
RS
R
R
BLL
Houk, K. N. et al. Tetrahedron. 1984, 40, 2257.
R = HR = ether
Substrate Generality
! Substrates that are base-sensitive can be coupled with different base/solvent combinations
Vinyl or Aryl Halides
Ar–X + R–BBN* Ar–R
Ar–X Alkene Yield Conditions
OMe
I
Br
Me(O)C Br
Me(O)C Br
Br
CO2H
1-octene
Me
Me
CN
8
OMe
Me
O O
90, 71
88, 71
98
52
77
a, b
a,b
c
c
c
a) PdCl2(dppf) (3 mol %), NaOH (3 equiv.), THF, refluxb) PdCl2(dppf) (3 mol %), NaOMe (3 equiv.), THF, refluxc) PdCl2(dppf) (3 mol %), K2CO3 (2 equiv.), DMF/THF, 50 °C
* from alkene (1 equiv.) and 9-BBN-H (1.1 equiv.)
13
Substrate Generality
! Vinyl bromides couple with retention of olefin geometry
Vinyl or Aryl Halides
vinyl–X + R–BBN* Ar–R
vinyl–X Alkene Yield Conditions
85
98
73, 79
81, 72
a
a
c
b, c
a) PdCl2(dppf) (3 mol %), NaOH (3 equiv.), THF, refluxb) PdCl2(dppf) (3 mol %), K2CO3 (2 equiv.), DMF/THF, 50 °Cc) PdCl2(dppf) (3 mol %), K3PO4 (1 equiv.), DMF/THF, 50 °C
* from alkene (1 equiv.) and 9-BBN-H (1.1 equiv.)
PhBr
Me
Br
Me
Me
MeO2CBr
O
Br
Me
Me
1-octene
1-octene
CN
8
PhS
Br
Me
Me
90 cchemoselective
hydroboration
Me
Me
Me
HH
H
AcO
chemoselectiveand diastereoselective
hydroborationMe
Me
CO2Me
Me
Substrate Generality
! Aryl and vinyl triflates are readily accessible from phenols or enolates
Vinyl or Aryl Halides
C(sp2)–X + R–BR2 Ar–R
C(sp2)–X Yield Conditions
92
65
67
64
a
a
b
a
a) PdCl2(dppf) (2.5 mol %), K3PO4 (1.5 equiv.), dioxane, 85 °Cb) PdCl2(dppf) (2.5 mol %), K3PO4 (1.5 equiv.), THF, reflux
56 Pd(OAc)2 (5 %), L* (7.5 %), Cs2CO3 (3 equiv.), THF, r.t.
MeO OTf
N
OTf
Me
Me OTf
Me
O
OTf
O
OTf
R–BR2
9-BBN
Me 9-BBN
O O
9-BBNMe
5
Me 9-BBN
EtO
OEt
9-BBN
N
TfO
Cbz
Me BOH
OH
93PdCl2(dppf) (5%), K2CO3 (2 equiv.), Ag2O (2 equiv.), toluene, 85 °C
PhO
PCy2
14
Substrate Generality
! 5- and 6-membered rings can be formed in an intramolecular fashion, larger rings were notpossible
Intramolecular Coupling
OTf
CO2Me CO2Me
76%
I
O O 70%
Ph
Br
Ph
Me
Me
Br
OO
Me
Me
OO
67%
84%
[a]
[b]
[b]
[b]
a) 9-BBN-H, THF; PdCl2(dppf), K3PO4, dioxane/THF, 85 °C b) 9-BBN-H, THF; PdCl2(dppf), NaOH, THF/H2O, 60 °C
! Exocyclic olefins can be formed
Br
Ph
9-BBN-H, THF;
PdCl2(dppf)NaOH
THF, 60 °C
Ph
83%
OTBS
9-BBN-H, THF;
PdCl2(dppf)NaOH
THF, 60 °CBr
BrMe
Me
OTBS
Soderquist et al. Tet. Lett. 1995, 36, 3119Suzuki; Miyaura et al. Tet. Lett. 1992, 33, 2571.
64%
Substrate Generality
! Unactivated aryl chlorides are famously less reactive towards oxidative addition
Aryl Chlorides
! heteroaryl and aryl chlorides with electron-withdrawing groups are considered activated
! complexation of aryl chlorides with Cr(CO)3 make them reactive partners in Suzuki couplings
Review of Aryl Chloride Pd-couplings: Fu, G. C.; Littke, A. F. Angew. Chem. Int. Ed. 2002, 41, 4176.
! Low reactivity usually attributed to the strength of the C–Cl bond
bond dissociation energies for Ph–X:
Cl = 96 kcal/mol Br = 81 kcal/mol I = 65 kcal/mol
! Despite remarkable progress of Ar–Cl couplings since 1998, only one example of B-alkyl-BBNcouplings to aryl chlorides by Furstner and Leitner (Synlett. 2001, 2, 290)
OMe
MeO Cl
B
OMe
(CH2)13Me
Pd(OAc)2 (2 mol%)
iPr • HCl (4 mol%)THF, reflux
OMe
MeO (CH2)12Me
81% yield
N N Cl
iPr • HCl
! electron-deficient and electron-rich aryl chlorides tolerated ingood yields (82-98%)
! alkyl, alkynyl, allyl, and cyclopropyl borates couple as well
MeO
O
Cl Cl NBn
Cl Ph
CO2Et
15
Potassium Alkyltrifluoroborates
! Initially prepared by Vedejs for complexing amino acids. R–BF3K are noted as a surrogate forR–BF2 (J. Org. Chem. 1995, 3020 and J. Am. Chem. Soc. 1999, 2460.)
! Early palladium-catalyzed Suzuki couplings with alkenyl, aryl, and alkynyl BF3K salts
R
N2BF4
Genet, J.-P. et al. Eur. J. Org. Chem. 1999, 1875.
I
BF4
R R
Xia, M.; Chen, Z.-C.Synth. Commun. 1999, 29, 2457.
! Molander reopens the field with Alkyl–BF3K couplings to C(sp2)–OTf in 2001
! Why are alkyl (and other) BF3K of interest??
– greater nucleophilicity than boronic acids or esters
– preparative on large scales (>200g)
– monomeric solids are readily isolated
boronic acids can be hard to isolate from the diol of the parent boronic ester
– long shelf lives
boronic acids have variable shelf lives, trialkylboranes are not stable
Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org. Chem. 2003, 68, 5534.
! Preparation of salts follows standard hydroboration procedures
R–BX2 + 2 KHF2
Et2O
H2OR–BF3K + 2 HX + KF (X = halogen, OH, OR, NR2)
Potassium Alkyltrifluoroborates
! Aryl/alkenyl triflates are slightly more reactive than C(sp2) bromides; C(sp2) iodides and chlorides are not compatible with this system.
X Ac TMS BF3KAc
TMS
PdCl2(dppf)•CH2Cl2 (9 mol%)
Cs2CO3 (3 equiv)THF:H2O (20:1), reflux
6-8 h70% (X = OTf)65% (X = Br)
I OTf n-Bu BF3KOTf
Me16%
I C(O)MeBF3K
Ph H C(O)Melack of reactivity in thetransmetalation step
! Secondary BF3K salts and electron-rich aryl bromides/triflates suffer from low reactivity
! Very good functional group tolerance is maintained: nitrile, ketone, ester, amide, and nitro
Br OTf n-Bu BF3K OTf
Me70%
16
Potassium Alkyltrifluoroborates
! Synthesis of tetra-substituted olefins
BF3KPdCl2(dppf)•CH2Cl2 (9 mol%)
Cs2CO3 (3 equiv)THF:H2O (20:1), reflux
TfO
Me
Bn
CO2Et
Me
Me
Bn
CO2Et
Me
75%
! Alkyl boronic acids function similarly under reaction conditions mechanistic implications?
Ph BR2
PdCl2(dppf)•CH2Cl2 (9 mol%)
Cs2CO3 (3 equiv)THF:H2O (20:1), reflux
TfO
O
Me
O
Me
Ph
84% (BR2 = BF3K)77% (BR2 = B(OH)2)
60% (BR2 = Bpin)is a similar catalytic cycle operable with alkyl BF3K cross-couplingas with alkyl borates?
! The reactive transmetalling species is not known yet
! slow internal hydrolysis of R–BF3K [!(11B)=5.6] to R–B(OH)2 [!(11B)=33.5]
! fluorinated species such as R–BF3–, R–BF2(OH)–, and/or R–BF(OH)2
– might be involved
! the reaction may be accelerating the reaction
conclusions to these questions await detailed kinetic and mechanistic investigations
Substrate Generality
! Cho and Shibasaki report cyclopentane asymmetric desymmetrizations using chiral ligands to givemodest enantioselectivity (Tet. Asymmetry. 1998, 9, 3751)
Asymmetric advances, Macrocyclizations
TfO
R 1. 9-BBN-H, THF;[Pd2(dba)3•CHCl3], L*
K2CO3, THF
2. 3M NaOH, 35% H2O2
OH
R
FePh2P
AcO
Me
FePh2P
AcO
Me
Ph2P
R = H
58% yield28% e.e.
R = CH2OTBS
42% yield31% e.e.
! Macrocyclizations can be done satisfactorily, dependent on the reaction conditions and substrates;even highly strained systems with transannular interactions
MeOTBS
MeO
I
MeOTBS
MeO9-BBN-H, THF;
PdCl2(dppf), AsPh3base, THF/DMFH2O (X equiv)
40% yield (3 equiv. Cs2CO3, 40 equiv. H2O)60% yield (3 equiv. TlOEt, 5 equiv. H2O)
O
O OH
OH
MeMe
Me
Me
phomactin A
Chemler, S. R.; Danishefsky, S. J. Org. Lett. 2000, 2, 2695.
17
sp3 - sp3 Cross-Coupling
! Suzuki discovers in 1992 that alkyl iodides and alkyl boranes can couple
C10H21–I C4H9–BBNPd(PPh3)4
K3PO4, dioxane50 °C
+ Me Me
850%
[O]
Miyaura, N.; Suzuki, A. et al. Chem. Lett. 1992, 691.
"alkyl bromides ... never provide the corresponding coupling products"
"The cross-coupling with inactivated alkyl halides is still difficult to achieve in high yields with palladium-catalyst,but the potentiality and synthetic utility thus suggested should be explored in the future"
I OBn R B(OH)2
Pd(OAc)2, PPh3K2CO3, Bu4NCl
DMF/H2O35 - 95%
R OBn
! Charette shows iodocyclopropanes can undergo oxidative addition.
Charette, A. B.; Giroux, A. J. Org. Chem. 1996, 61, 8718.
! Fu breaks open this field with his inital report of alkyl bromide and alkyl borane coupling undervery mild conditions
C10H21
BrBBN
C6H13
4% Pd(OAc)28% PCy3
1.2 eq. K3PO4•H2OTHF, 23 °C
C10H21
C6H13 85% yield<2% !-H elim.
Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099.
Fu expands the scope of the alkyl-alkyl coupling
! Fu discovers the first Suzuki cross coupling of alkyl bromides in 2001
Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099.
X
9-BBN-H
THF
Br Y
Pd(OAc)2, PCy3K3PO4•H2OTHF, 23 °C
XY
! PCy3 is uniquely effective; triarylphosphines, arsines, trialkylphosphines, and bidentate ligands do not work (Pi-Pr3 gives 68%)
! functional group tolerant: amines, alkenes, esters, alkynes, ethers and nitriles
! alkyl bromides react faster than alkyl chlorides
TESO BBN
5
Cl Br
6
Cl
6OTES
5
81% yield
! water is essential - anhydrous K3PO4 gives almost no reaction
! NMR studies are consistent with hydroxy-bound borate adduct as reactive species
72 - 93% yields
! vinyl boranes serve as coupling partners
BBN
Br Me
11Me
11
66% yield
! Cloake (U. Sussex) - same transformation with Pd(dba)2 (3%), iPr•HCl (3%), KOMe, TBAB (10%), in toluene at 40 °C (Tet. Lett. 2004, 45, 3511.)
Greg Fu
18
Fu expands the scope of the alkyl-alkyl coupling
! Alkyl chlorides are the next substrate for Fu to solve
OEt
EtOCl
BnO
9-BBN-H
5% Pd2(dba)3, 20% PCy31.1 equiv. CsOH • H2O
dioxane, 90 °C
BnO OEt
OEt
70% yield
! again, PCy3 is unique for this transformation although P(c-C5H9)3 and P(i-Pr)3 can work
! N-heterocyclic carbenes (IMes) only gives minor reaction
! functional group tolerant: aryls, ethers, acetals, olefins, amines, nitriles, and esters
! Alkyl chlorides down, alkyl tosylates up.
Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 1945.
OTsMe
O
6BBN OTES
11
4% Pd(OAc)216% P(t-Bu)2Me
1.2 equiv. NaOHdioxane, 50 °C
Me
O
16OTES 55% yield
R = i-Pr Et Me
PCy2R
Pt-Bu2R
Cy
44% 70% 48% 46%
<2% <2% 78% --
! oxidation addition proceeds with inversion and reductive elimination proceeds with retention
"...we have not yet determined the origin of this striking dependence of reactivity on phosphane strucure"
! [HP(t-Bu)2Me]BF4 is a surrogate for air-sensitive P(t-Bu)2Me
Netherton, M. R.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 3910.
Fu ...he keeps going and going.....
! Alkyl bromides with alkyl boronic acids instead of alkyl boranes
! need to use a more reactive ligand and different solvent for solubility of reactants
Br
O
O
BOH
OH
5% Pd(OAc)210% P(t-Bu)2Me
KOt-But-amyl alcohol
23 °C
O
O
97% yield93% with [HP(t-Bu)2Me]BF4
! function group tolerant for alkyl bromide
! scope of boronic acid compenent limited to aryls, BHO
OH
HOBMe
OH
Meand
Kirchoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662.
! Secondary alkyl bromides and iodide react as well
Br (HO)2B Ph
4% Ni(COD)28% bathophenanthroline
1.6 equiv. KOt-Busec-butanol, 60 °C
Ph
N N
Ph Ph
Zhou, S.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340.
! unactivated primary and secondary iodides react in 62 - 75% yield
! boronic acid scope limited to aryl systems for bromides, aryl and alkenyl systems for iodides
19
Alkyl Boranes in Natural Products
! Danishefsky - Epothilones (J. Am. Chem. Soc. 1999, 121, 7050.)
Me
OTBS
Me
MeO
OTPS
Me
Me
OMe
1. 9-BBN-H, THF2. Pd(dppf)Cl2 Cs2CO3, AsPh3 DMF/H2O, 23 °C
S
N
Me
MeOAc
MeO
OMe
Me
MeMe
OTPSOTBS
Me
S
N
Me
MeOAc
I
56% yield
S
N
Me
MeO
Me
MeMe
OTPSOTBS
Me
O
epothilone A
! macrocyclization approaches did not work
! Moore - Squalene Epoxidase Inhibitors (J. Am. Chem. Soc. 1992, 114, 360.)
Me
Me
Me
Me
Me
Me
IF
Me
Me
Me
Me
Me
Me
MeF
BO
Me
Pd(PPh3)4NaOH, THF82% yield
Alkyl Boranes in Natural Products
! C. Lee - Kendomycin (J. Am. Chem. Soc. 2004, 126, 14720.)
Me I
Me
OMe
HO
Me
O
BMe
Me
TBSO
OMe
Me
O
MeO
OMe
HO
Me
O
Me
Me
TBSO
OMe
Me
O
Me
MePd(dppf)Cl2
Et2O/THF/DMF
K3PO4
Me
Me
OMe
HO
Me
Me
Me
HO
O
Me
O
OH
86% yield
Kendomycin
! J. Marshall - Discodermolide (J. Org. Chem. 1998, 63, 7885.)
O O
Me
PMP
Me
O OMe
OMOM
Me
Me
I
MOMTBS
Me
B
O
Me
OTES
Me
OMe
O O
Me
PMP
Me
O OMe
OMOM
Me
MeMOMTBS
Me
OPMB
Me
OTES
Me
PdCl2(dppf)K3PO4
O
HOMe
MeO
Me
Me
OH
Me
OH
Me
OH
Me Me
O
O
NH2
PMB
74% yield
Discodermolide
20
Alkyl Boranes in Natural Products
! Sasaki - relied heavily on B-alkyl Suzuki coupling for polyether natural products like brevetoxins, ciguatoxins, and gambierol.
O
OBn
BnO OTBS
OMOM
O
OBn
BnO OTBS
OMOM
OOP
PhO
PhO
O
OBn
OBn
1) 9-BBN-H2) Pd(PPh3)4DMF, 50 °C
O
OBn
OBn
ciguatoxinB
D
first example of vinyl phosphonate used for B-alkyl Suzuki-Miyaura coupling
Org. Lett. 1999, 1, 1075.
! Trost - Sphingofungin F (J. Am. Chem. Soc. 1998, 120, 6818.)
MeOO
5 4
1) 9-BBN-H2) PdCl2(dppf)AsPh3, Cs2CO3DMF/THF/H2O
O
N
O
Me
Ph
OI
O
N
O
Me
Ph
O
MeOO
5 4
Me
5 4
O
OPMB
OPMB
OH
OH
OH
COO
NH3Me
B-Alkyl Suzuki CouplingsConclusion
! Catalytic cycle is generally well understood, however each reaction should be consideredon a case-by-case basis.
! B-alkyl Suzuki-Miyaura couplings are a very powerful tool for C–C bond formation
Relevant and Comprehensive Reviews:
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. "The B-alkyl Suzuki-Miyaura cross-coupling reaction: a versatile C–C bond-forming tool." Angew. Chem. Int. Ed. 2001, 40, 4544-4568.
Miyaura, N. "Metal-Catalyzed Cross-Coupling Reactions of Organoboron Compounds with Organic Halides." Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley-VCH, Weinheim, 1998, Ch. 2.
Miyaura, N; Suzuki, A. "Transition-Metal Systems Bearing a Nucleophilic Carbene Ancillary Ligand: fromThermochemistry to Catalysis." Chem. Rev. 1995, 95, 2457-2483.
! Catalyst-controlled chirality - one example
! Advancements have been rapidly reported in the past 20 years
Echavarren, A.M.; Cardenas, D. J. "Mechanistic Aspects of Metal-Catalyzed C,C- and C,X-Bond-Forming Reactions." Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley-VCH, Weinheim, 1998, Ch. 1.
! B-alkyl Suzuki couplings can be used in complex natural products due to functional groupcompatability and the ability to alter conditions accordingly